Radiopaque derivatives of triiodobenzoic acid with heterocyclic side chains

ABSTRACT

Compounds of the formula R - R&#39;&#39;, wherein   R1 is alkylene or oxaalkylene having 2 or 3 carbon atoms; R2 is -(CH2)a- or -CO-; R3 is hydrogen or lower alkanoyl; R4 is hydrogen, lower alkyl, or R-NH-CO-R5-CO-, R3 being hydrogen when R4 is R-NH-CO-R5-CO; R5 is alkylene or polyoxaalkylene having 4 to 8 carbon atoms; A IS ZERO OR ONE, AND -(CH2)a is a single carbon-to-carbon bond when a is zero; and A is hydrogen or a non-toxic metal or amine, the compound being water-soluble when A is metal or amine; have been found to be well tolerated, effective contrast media for the X-ray investigation of blood vessels, the urinary tract, and the gall bladder when used parenterally.

United States Patent 1 Felder et al.

[ May 13, 1975 RADIOPAQUE DERIVATIVES OF TRIIODOBENZOIC ACID WITH HETEROCYCLIC SIDE CHAINS [75] lnventors: Ernst Felder; Davide Pitre, both of Milan, Italy [73] Assignee: Bracco Industria Chimica, Societa per Azioni, Milan, lta'ly [22] Filed: Apr. 7, I969 [2|] Appl. No.: 814,193

[30] Foreign Application Priority Data May 2, i968 Switzerland 6625/68 [52] U.S. Cl 260/293.64; 260/246 B; 260/2472; 260/293.76; 260/293.77; 260/293.79;

[51] Int. Cl. C07d 29/28; C07d 29/30 [58] Field of Search....... 260/326.3, 293.77, 293.79, 260/29'3.76, 293.64

[56] References Cited OTHER PUBLlCATlONS Chemical Abstracts, Vol. 58, pp. 4474-4475, (1963).

Primary Examiner-Donald G. Daus' Assistant Examiner.lose Tovar Attorney, Agent, or Firm-Hans Berman [57] ABSTRACT Compounds of the formula R R, wherein R is alkylene or oxaalkylene having 2 or 3 carbon atoms;

R is hydrogen or lower alkanoyl;

R is hydrogen, lower alkyl, or RNHCOR CO, R being hydrogen when R is RNHCOR -,-CO;

R is alkylene or polyoxaalkylene having 4 to 8 carbon atoms;

a is zero or one, and (Cl-l is a single carbon-to-carbon bond when a is zero; and

A is hydrogen or a non-toxic metal or amine, the compound being water-soluble when A is metal or amine; have been found to be well tolerated, effective contrast media for the X-ray investigation of blood vessels, the urinary tract, and the gall bladder when used parenterally.

19 Claims, No Drawings RADIOPAQUE DERIVATIVES OF TRIIODOBENZOIC ACID WITH HETEROCYCLIC SIDE CHAINS This invention relates to X-ray contrast media, and particularly to organic compounds high in iodine content, their preparation, and their use.

Many iodine-bearing organic compounds have heretofore been proposed for use in the radiography of body cavities other than the intestinal tract. Those compounds which can only be applied orally, are usually resorbed in the intestine to a small part, and X-ray images of adequate density are not readily produced with amounts of contrast agent small enough not to cause diarrhea and other side effects. The known contrast agents recommended for parenteral application in cholecystography are known to produce serious accidents in some cases (see La Radiologia Medica 52 (July 1966) 626627).

The primary object of the invention is the provision of radiopaque compounds of a type not known heretofore which are well tolerated ineffective doses parenterally applied, and some of which are particularly effective in cholecystography. formula COCA C0011 l L, I a I a /CO\ I (ca l l H v- 2 s l..-co-.t co-ila (Cll -Iv R l CI The compounds of the invention are derivatives of 2,4,6-triiodobenzoic acid whose benzene ring carries a side chain. A heterocyclic ring in the side chain includes the radical CONCH whose nitrogen atom is bound to the benzene ring of the triiodobenzoic acid either directly or through a methylene group, that is, a carbon chain having not more than one member. More specifically, the compounds of the invention have the formula R R, wherein so R is alkylene or oxaalkylene having 2 or 3 carbon atoms; R is -(CH ),,or CO-; R is hydrogen or lower alkanoyl'.

R is hydrogen, lower alkyl, or RNHCO R CO, R being hydrogen when R is R-N- HCO-R CO;

R is alkylene or polyoxaalkylene having 4 to 8 car bon atoms;

a is zero or one. and (CH is a single carbon-tocarbon bond when a is zero; and

A is hydrogen or a non-toxic metal or amine, the compound being water-soluble when A is metal or amine;

The heterocyclic ring may thus be the radical of a lactam of aminobutyric or of one of the aminovaleric acids or of a morpholinone. The compounds of the invention in which A is hydrogen are insoluble or only slightly soluble in water and are used parenterally in the form of their water-soluble non-toxic salts with metals and amines. The alkali metal salts and salts of the free acids of the invention with the alkanolamines commonly employed in medicinal compounds as inert cat ions for use with active anions are readily soluble in wa ter. The sodium and lithium salts are best tolerated among the alkali metal salts and very easily soluble in cold water. The calcium and magnesium salts of some compounds of the invention have adequate solubility in water and are non-toxic. Typical suitable alkanolamines are N-methylglucamine and diethanolamine, but others are equally effective.

Compounds of the invention in which R is N- H-COR CONHR, that is, compounds of the tend to accumulate preferentially in the gall bladder when injected or infused into the veins or muscles of a warm-blooded animal such as man, and are therefore preferred for cholecystography. Those compounds which have only one triiodobenzoic acid moiety in their molecules are preferred for urography and angiography. When suitably compounded, the compounds of the invention may also be employed as contrast media for bronchography, hysterosalpinogography, and for the visualization of other body cavities in which iodine bearing organic compounds have been used heretofore. All compounds of the invention are well tolerated when applied intravenously.

The manner in which compounds of the invention having a single triiodobenzoic acid moiety are excreted almost entirely with the urine as is preferred in urography is shown in Table l which identifies the compounds by capital letters and refers to Examples given hereinbelow of methods for preparing the compounds. The Table lists toxicity values determined by standard methods on mice and expressed as DL in grams of compound per kilogram of mouse weight. It also lists the percent fraction of the compound which was found in the urine and in the bile of rabbits three hours after the intravenous injection of lOO mg of the compound per kilogram of rabbit weight.

TABLE l Compound Toxicity Bilc G LN-Butyrolactamyl-5acctyl amino-2.4.6-triiodohcnzoic TABLE l-Continued Compound Toxicity Secretion 7! into DL g/kg Urinc Bilc acid (Ex.7) ll.(] (18 0.6 .I 3-N-Butyrolactamylmethyl- -5 acetylarnin0-2,4 6-triiodohenzoic acid (Ex.l) 9.6 85 1.2 X 3-NButyr0lactamyl-5 acetylaminomethyl-ZA,o-triiodobenzoic acid (EiLlZl 10.0 83 3 Y 3-(Morpholin0n-3'-yl-4')-5- -acetylaminomethyl2,4.6 triiodobenzoic acid(Ex. [9) 10.0 75 3 H 3-(Morpholinon-3'-yl-4')-5- -acetylaminc-2,4,6-triiodobcnzoic acid (EXBl 8.0 57 2 E 3-(Morpholinon-3-yl-4')-5-N' -methylcarbamyl 2,4.6-triiodobenzoic acid (Ex.5) 9.6 52 l B (Morpholinon-3'-yl-4')-2.4.6

triiodobenzoic acid [Ex.2) 86 1.4

The compounds of the invention which have two triiodobenzoic acid moieties in their molecules and are generally preferred for cholecystography are also useful for intramuscular injection. The toxicities and secretion values of representative compounds of this group are listed in Table 2, the data being arrived at as described above with reference to Table l. Corre sponding data for two known cholecystographic con trast media are also listed.

TABLE ll Compound Toxicity Secretion into DL g/kg urine bile N Azelaic acid bis(3-N-butyrolact amylmethyficarboxy-ZAli-triiodoanilidc)(Ex.l4] 3.8 45 O Scbacic acid bis(3-N-butyr0lactamylmethyl-5-carboxy2,4,fi triiodoanilide) (Ex.l4) 2.35 55.7 ll.9 M Suberic acid bis(3-N-butyrolactamyl methyl-5-carboxy-2,4.6-triiodo anilide) (Ex.l3) 6.4 SI 16 R 4,7-Dioxadecane-l,lO-dioic acid bis[3-N-butyrolactamylmethyl -5carboxy-2.4,6-triiodoanilide) tEx.14) 10.7 40 17.5 T 4.7 Dioxadecanel,lO-dioic acid bis 3-N-6-valerolactamylmethyLS- -carboxy2.4,6-triiodoanilide) (Ex.l5) 6.0 34 27 S 4,8-Dioxaundecane l,l l-dioic acid bis 3-N-butyrolactamylmethyl-5- carboxy-2Ab triiodoanilide) lEx.l4] 10.0 52 30 ll lodipamide 2.38 37 38 1A loglycamic acid 3.75 3(1 41 1 dog 2 cat a 100 mg tested compound injected intravenously per kg.

b 165.6 mg iodine per kg, intravenous injection c 165.6 mg iodine per kg by intravenous infusion over 4 hours.

TABLE I" Com- Note pound Cholccystographic lndcx After l hr. 2 hrs. 4 hrs. 6 hrs. 8 hrs. 24 hrs.

Median value 1.75 Median value 3.5 (intramuscular injection] The compounds of the invention are synthesized from triiodobenzoic acid derivatives of the formula in which R" is hydrogen, nitro, amino, acylamino, acylaminomethyl, N-alkylacylamino, N-alkylcarbamyl, or alkylenediacylamino, the term alkylene including oxaalkylenes, by reaction with a reactive acyl derivative of an acid of the formula is formed on the benzene ring of the starting compound. The side chain is thereafter cyclized in an alkaline medium. If X X X are initially different from iodine, they are converted to iodine, R is converted to the desired R by methods conventional in themselves if initially different from R, and the carboxyl group on the benzene ring may be converted to -COOA in which A is different from hydrogen.

When R is nitro, the nitro group may be converted to amino by hydrogenation, whereby X X X are simultaneously converted to hydrogen if initially different from hydrogen. and said hydrogen is converted subsequent to the hydrogenation to iodine by reaction with a complex iodinechlorine compound in a manner conventional in itself.

In preparing the compounds of the invention which have two triiodobenzoic acid moieties in their molecules, that is those in which R is RNH-COR- ,CO-NH. it is preferred to react a starting compound of the formula with a reactive diacyl derivative of a dicarboxylic acid having the formula HOOCR COOH in an approximate ratio of two moles of the starting compound to one mole of the diacyl derivative at a temperature of 20 to 250C. in the presence of an inert solvent until the amino groups on the two molecules of the starting compound are linked to constitute the group N HCOR =,CONH-, and to convert the carboxyl group of the starting compound to -COOA if different from the desired -COOA. The reactive diacyl derivatives of the dicarboxylic acids which are employed to best advantage are the acyl halides, the acyl azides, and the anhydrides.

If it is desired to prepare compounds of the invention in which R is R and R being as defined above, and R being lower alkyl, alkylating agents such as lower-alkyl halides, sulfates, and sulfonates are reacted with compounds of the invention in which R' is R NHR The manner of preparing and using the compounds of the invention will become evident from the following Examples, but it will be understood that the invention is not limited to the compounds specifically referred to. The numerous closely related compounds embodying the aforementioned group CONCH in a heterocyclic ring whose nitrogen atom is linked directly or through a single methylene group to the benzene ring of a 2,4,6-triiodobenzoic acid derivative which are arrived at by permutation of substituents and substitution of other lower alkyl radicals for the methyl and ethyl groups more specifically disclosed and preferred, are prepared by methods obvious from the Examples and are equally effective. The sole instance of a critical limitation on the length ofa carbon chain has been pointed out above.

EXAMPLE I 3-N-Butyrolactamyl2,4,6-triiodobenzoic acid (Compound A) 6.2 g 3y'chlorobutyramido2,4,6-triiodobenzoic acid (0.01 mole) were dissolved in ml 2.67 N aqueous potassium hydroxide, and the solution was kept at 70C. for three hours. cooled to ambient temperature, diluted with 30 ml water. and extracted with diethyl ether. The ether extract was discarded, and the aque ous phase was exposed to a vacuum to remove the ether therefrom and acidified with hydrochloric acid, whereby crude Compound A was precipitated. It was recovered in an amount of5.5 g (94.4% yield) and had a melting point of 260 to 265C.

The pure Compound A recrystallized from 80 ml methanol melted at 270 272C. and was identified by elementary analysis.

Calculated for C HJ NO 2 2 6671 C; Found: 2.62

water 5:1:l gave a single spot at R 0.62. The free acid is insoluble in water. readily soluble in warm methanol or ethanol. The salts with sodium, lithium ethanolamine, diethanolamine, N-morpholine. N- methylglucamine, and like non-toxic cations are readily soluble in water.

The 3-y-chlorobutyramido-2,4,6-triiodobenzoic acid was prepared by heating 41.2 g dry 3-amino-2,4,6- triiodobenzoic acid in about 300 ml boiling anhydrous chlorobenzene with 14 g y-chlorobutyryl chloride for two hours. The precipitate formed was reprecipitated from ethyl acetate with petroleum ether in a yield of 40.3 g M.P.208-2l0C. R, 0.57 with the above solvent system. The substrate was silica gel GF 254 (Merck) which was used throughout these Examples.

EXAMPLE 2 3-(Morpholinon-3'-yl-4)-2,4,6-triiodobenzoic acid (Compound B) Compound B was prepared from 6.35 g (0.0l mole) 3-(B-chloroethoxyacetylamino)-2,4,6-triiodobenzoic acid of the formula CH ClCH O-CH CO-Nl-l-CA-lh-COOH by dissolving the acid in 15 ml 2.67 N potassium hydroxide. Ring closure occurred spontaneously at ambient temperature within 20 hours, and the reaction mixture was then worked up as described in Example l to 5.6 g crude Compound B (93.5% yield) which melted with decomposition at 270C.

The pure compound recrystallized from 300 ml ethanol melted at 280C. (decomp), and had an R, value of 0.24 under the conditions of Example 1. It is insoluble in water, chloroform, and ethyl acetate, and only sparingly soluble in the lower alkanols. It was identified by its iodine content of 63.53% (63.57% calculated for C H I NO The necessary 3-(B-chloroethoxyacetylamino) 2,4,6- triiodobenzoic acid was prepared by heating 20.6 g 3-amino-2,4,6-triiodobenzoic acid with 7.6 g B-chloroethoxyacetyl chloride in ml dioxane at 90C. for three hours, and pouring the reaction mixture into water. The precipitate formed was recrystallized from ethanol and melted at 231C. (decomp) The yield was l5.8 g (62%).

EXAMPLE 3 3-N-8-Valerolactamyl-2,4,6-triiodobenzoic acid (Compound C) A solution of 20.6 g 3-amino-2,4,6-triiodobenzoic acid (0.04 mole) in 40 ml dimethylacetamide was heated to 90C., and 10 g (0.05 mole) S-bromovaleryl chloride were added. The reaction mixture was stirred at 90C. for three hours, cooled to room temperature, and poured into 300 ml water to precipitate 26 g crude 3-N-8-bromopentanoyl-amino-2,4,6-triiodobenzoic acid (M.P.l20 l30C.)

This crude acid was dissolved in 50 ml 2.l2 N aqueous potassium hydroxide. and the solution was left to stand at ambient temperature for 16 hours. It was then diluted with water to 250 ml, adjusted to pH 4. and extracted with a little ethyl ether to remove impurities. The aqueous phase was exposed to a vacuum to remove ether, and strongly acidified to precipitate crude Compound C in an amount of 21 g (87% yield). M.P. 233 235C.

When recrystallized from 200 ml ethanol, the pure Compound C melted at 235 to 238C. R,= 0.29 (butyl Calculated for C H ul N n Found:

Eqwt. 597;

The sodium and N-methylglucamin salts were prepared from equivalent alcohol solutions of the acid and base by evaporation of the solvent and are readily soluble in equal weights of water.

EXAMPLE 4 3-l l-Butyrolactamyl-5-N-methylcarbamyl-2.4,6 triiodobenzoic acid (Compound D) 8.4 g y-chlorobutyryl chloride (0.06 mole) were added drop by drop to a suspension of 28.6 g (0.05 mole) 3-amino5-N-methylcarbamyl-2.4,6- triiodobenzoic acid in 30 ml dimethylacetamide at 90C. The mixture was stirred for three hours at 90C., cooled, and poured into 500 ml water to precipitate 27.6 g 3-N-rchlorobutanoylamino-Z,4.6-triiodo-5-N- methylcarbamylbenzoic acid having a melting point of more than 250C. and an equivalent weight of 679 as compared to the expected value of 676.5.

The material was dissolved in 60 ml 2.5 N aqueous potassium hydroxide. The solution was left to stand for about 20 hours at room temperature, diluted with 200 ml water. adjusted to pH 4, decolorized with active carbon, and strongly acidified with hydrochloric acid at 50C.

20 g Compound D (63% yield) were precipitated. A solution of the crude compound in the necessary minimum of concentrated ammonium hydroxide solution was poured into an excess of dilute hydrochloric acid at 50C. whereby the Compound D of M.P.25 lC. was precipitated. It gave an R; value of 0.5! on silicagel with butanol/glacial acetic acid/water 3:2: I, was insoluble in chloroform, somewhat soluble in water (2-470). readily soluble in lower alkanols. It was identified by elementary analysis.

Calculated for C H lfl h s 24.40% C; 59.50% I Found: 23.8

The sodium salt dissolves in water to about 40 g/dl, the glucamin salt is soluble in an equal weight of water.

EXAMPLE 3-(Morpholinon-3'-yl-4)-5-N-methylcarbamyl-2.4.6- triiodobenzoic acid (Compound E) Compound E (68% yield) were obtained. M.P.250C. R,= 0.58 on silica gel with butanol/glacial acetic acid/- water 3:]:1.

The free acid is insoluble in chloroform, slightly soluble in water. cold methanol and cold ethanol, readily soluble in boiling methanol and ethanol. It was identified by elementary analysis and by its equivalent weight.

Calculated for C H I N O Eq.wt. 658; 23.80% 58.04% I C: Found: 656 23.18 56.35

The sodium and Nmethylglucamine salts of Com pound E were prepared as described above are are soluble in equal weights of water at 20C.

EXAMPLE 6 3-N-B-Valerolactamyl-5-N-methylcarbamyl-2,4,6- triiodobenzoic acid (Compound F) 22.05 g 3-N-8-Bromopentanoylamino-5-N- methylcarbamyl-2.4,6-triiodoben2oic acid were dissolved at 20C. in 45 ml 2.7 N aqueous potassium hydroxide. The solution was stored 15 hours. diluted with 250 ml water, adjusted to pH 5. decolorized with active carbon, and strongly acidified to precipitate crude Compound F in an amount of 12.8 g (65.5% yield). M.P.250' 253C.

It was purified by dissolution in a small amount of ammonium hydroxide solution, and the ammonium salt was precipitated by salting out with ammonium chloride, dissolved in pure water, and converted to the acid by precipitation with hydrochloric acid. The purified acid was identified by its equivalent weight and elementary analysis.

Calculated forC H l N O Eqwt. 6S4; 25.7|% 58.22%!

Found: 654 25x2 58.03

EXAMPLE 7 3-N-Butyrolactamyl-5-acetylamino2.4.6- triiodobenzoic acid (Compound G) 28.6 g 3-Amino-5-acetylamino2.4.64riiodobenzoic acid (0.05 mole) were suspended in 40 ml dimethylac etamide. and 8.4 g (0.06 mole) B-chlorohutyryl chloride were added to the suspension at C. The mixture so obtained was stirred at l00C. for three hours.

9 cooled. and poured into 600 ml water. 26g 3-N-6- chlorobutyrylamino-S-acetylamino-2.4,6 triiodobenzoic acid were recovered in solid form.

M.P.220 223C. Equivalent weight 672 (calculated: 675). The intermediate was dissolved in 50 ml 3 N potassium hydroxide, and the solution was stored overnight at room temperature to close the ring. Compound G was precipitated when the solution was made strongly acid, and was purified by dissolution in ammo nium hydroxide solution and precipitation with hydrochloric acid. The pure Compound G obtained in an amount of 17.5 g (55% yield) had a melting point of 250C. and an R; value of 0.45 with butanol/glacial acetic acid/water 3:1:1, and was identified by its equivalent weight and elementary analysis:

Calculated fur C, H,,l;,N O.,: Eq.wt. 640; 24.40% 59.52% I Found: 640 24.42 59.50

The acid is insoluble in water and chloroform, soluble in boiling ethanol, readily soluble in boiling methanol. The sodium and N-methylglucamine salts dissolve in equal weights of water at 20C.

EXAMPLE 8 3-(Morpholinon-3-yl-4')-5-acetylamino-2,4,6- triiodobenzoic acid (Compound H) Using the general procedure described in Example 7, 28.6 g 3-amino-5-acetylamino-2,4,6-triiodobenzoic acid and 9.4 g fi-chloroethoxyacetyl chloride were reacted to 29 g 3-N-8-chloroethoxyacetylamino-S- acetylaminc-2,4,6-triiodobenzoic acid. M.P.250C. Ring closure was brought about in 50 ml 3.3. N aqueous potassium hydroxide, and the crude Compound H was purified by mixing a suspension of the acid in warm ethanol with an equivalent amount of cyclohexylamine, whereby the acid was dissolved, and the cyclohexylamine salt was precipitated upon cooling. The pure Compound H recovered from an acidified aqueous solution of the cyclohexylamine salt weighed 18 g (55% yield) and had a melting point of 250C. R 0.59 with butanol/glacial acetic acid/water 3:211. It was identified by its equivalent and elementary analysis as c H l N- Calculated: Found:

Eqwt.

It is insoluble in water, chloroform, and the lower alkanols, but the sodium and N-methylglucamine salts readily dissolve in eqial weights of water.

EXMAPLE 9 3-N'butyrolactamylmethyl-5-amino-2,4,6- triiodobenzoic acid (compound l) The precipitate formed was dissolved in liters 5' so dium bicarbonate solution, and the solution was decol' orized with active carbon and strongly acidified with hydrochloric acid to precipitate 700 g El-N-ychlorobutyrylaminomethyl-5-nitro-6-chlorobenzoic acid of MT. I23 130C. having an equivalent weight of335, as calculated. and an R value of 0.40 in chloroform/glacial acetic acid 4:1.

The 700 g (2.09 mole) of the last-prepared com pound were dissolved in 3,000 ml water containing 540 g (8.36 mole) 85% potassium hydroxide, and the solution was left to stand overnight at ambient temperature, diluted with water to 10 liters, and strongly acidified with hydrochloric acid to precipitate 436 g 3-N- butyroiactamylmethyl-S-nitro-6-chlorobenzoic acid (71% yield) having a melting point of 227 229C, an equivalent weight of 300.5 (calculated: 298.7), and an R, value of 0.30 with butyl acetate/glacial acetic acid/- water 5:111

72 g 3-N-butyrolactamylmethyl-Smitro-fichlorobenzoic acid (0.24 mole) were dissolved in 5 liters water containing 240 ml 1 N NaOH and hydrogenated in the presence of9 g 10% palladium-carbon catalyst at 50 55C., while the pH was held between 6 and 7 by the gradual addition of 240 ml N sodium hydroxide solution to the hydrogenation mixture. When enough hydrogen had been absorbed for converting the nitro group to the corresponding amino group and for eliminating chlorine from the benzene ring, the catalyst was removed by filtration, and the filtrate containing the sodium salt of 3-N-butyrolactamylmethyl 5- aminobenzoic acid was poured into 40 liters water containing 300 ml 36% hydrochloric acid.

800 M] N KlCl solution were added gradually over a period of one hour to the solution with agitation at 50C., and the mixture was then kept at that temperature for 15 hours to complete the iodation. The crude Compound I was filtered off with suction and dissolved in sodium hydroxide from which it was again precipitated with hydrochloric acid. It was again dissolved in an equivalent amount of aqueous sodium hydroxide, and the sodium salt was precipitated by salting out with sodium chloride. Ultimately, the pure acid was ob tained by decomposing a solution of the purified sodium salt with hydrochloric acid. The amount of free acid recovered was l00.5 g (68% yield). M.P.250C. R; 0.37 (witl' ethyl acetate/isopropanol/ammonium hydroxide 11:7:4).

Calculated for C,,H ,l N,O;,: EqWt. 612; 23.55% 62.22% 1 Found: 6l0 23.60 62.32

Compound I is insoluble in wate methanol, ethanol, chloroform, slightly soluble in dioxane (1.5% at 20C., 3% at 96C. The sodium and N-methylglucamine salts readily dissolve in equal weights of water.

EXAMPLE l0 3-N-Butyrolactamylmethy1-5-acetylamino-2,4.6- triiodobenzoic acid (Compound .1)

9.15 g Compound i were heated in 75 ml acetic anhydridc to 50C., 0.2 ml sulfuric acid were added. and the mixture was stirred at C. for 30 minutes, whereupon the excess of acetic anhydride was evaporated in a vacuum. The residue was dissolved in dilute sodium hy droxide. and the solution was kept at 70C. for one hour. additional sodium hydroxide solution being added from time to time to maintain an alkaline reaction. Compound J was precipitated when the reaction mixture was ultimately acidified with hydrochloric acid. and 7.3 g were recovered (75% yield). M.P.260 265C. R, 0.18 (ethyl acetate/isopropanol/conc- .ammonium hydroxide llz7z4).

Calculated for C H l -.N,O Eqwt. 654; 25.7l% 58.22% I Found. 650 25.78 58.42

The free acid is insoluble in water, methanol, ethanol, ethyl acetate, and chloroform. The sodium and N- methylglucamine salts are soluble in equal weights of water at 20C.

EXAMPLE ll 3-N-Butyrolactamylmethyl-5-N-butyrolactamyl-2,4,6- triiodobenzoic acid (Compound K) 4.6 g y -Chlorobutyryl chloride were added at 90C. to l8.4 g Compound I in 30 ml dimethylacetamide, and the mixture was stirred three hours at 90C. and poured into 200 ml water to precipitate 20.5 g 3-N- butyrolactamylmethyl-S-N-'y-chlorobutyrylamino- 2,4,6-triiodobenzoic acid. M.P. high-melting 193C. The acid was dissolved in 50 ml 2.5 N aqueous potas sium hydroxide solution, and crude Compound K was precipitated on the next day when the solution was diluted with 200 ml water and acidified with hydrochloric acid. The 14 g crude Compound K (70% yield) having a melting point of [90 200C. were dissolved in 60 ml boiling ethanol. When the solution was refluxed for a few minutes, Compound K was converted to its stable, high-melting crystalline modification which partly precipitated from the alcoholic solution while it was still warm. The yield was 1 l g (55%), the melting point higher than 255 C., R, 0.24 (ethyl acetate/isopropanol/ammonium hydroxide 55:35:20).

Calculated for C,,,H,,,I N O Eq.wt. 680; 28.26% 55.9% I

C; Found: 684 28.3] 55.85

The free acid is insoluble in water and chloroform. slightly soluble in cold lower alkanols, somewhat soluble in boiling methanol and ethanol. The sodium and Nmethylglucamine salts dissolve in equal weights of water at 20C.

EXAMPLE l2 3-N-5-Valerolactamylmethyl-Samino-2.4.6 triiodobenzoic acid (Compound L) When 46 g (0.2 mole) 3-aminomethyl-S-nitro-f chlorobenzoic acid in 320 ml dioxane were reacted with 476g (0.24 mole) S-bromovaleryl chloride for six hours at 90C. in the manner described in Example 9 with reference to the adjacent lower homolog, 58 g 3- N--bromovalerylaminomethyl5-nitro-6 chlorobenzoic acid of M.P.l23C. and equivalent weight 380 (calculated 393) were obtained. and were dissolved in 180 ml 3.3 N aqueous potassium hydroxide solution. The corresponding lactam derivative was precipitated from the diluted solution on the next morning by means of hydrochloric acid in an amount of 35 g l.l2 mole).

When recrystallized from ethanol, the intermediate product had a melting point of 250C. an equivalent weight of 3 l4.5 (calculated: 312.7). and a R, value of 0. l 4 in a thin layer chromatogram developed with chloroform/glacial acetic acid :5.

25 g (0.08 Mole) of the intermediate were hydrogenated in the presence of 3 g palladium-carbon catalyst in dilute, weakly alkaline, aqueous solution, and the hydrogenated acid was iodated in the acidified solution as described above with 330 ml N KlCl 2 solution at 50C. The iodation mixture yielded 3 l .5 g (63%) Compound L of M.P. 163C. and equivalent weight 623 (calculated: 626). It was converted to the high-melting, stable, crystalline modification by boiling in ml methanol.

Calculated for C H I MO Eq.wt. 626; 24.94% 60.82% l Found: 626 24.9l 60.80

A thin-layer chromatogram developed with ethyl acetatelisopropanol/ammonium hydroxide l 117:4 gave an R; value of 0.35. The acid is insoluble in water and chloroform, slightly soluble in lower alkanols. The sodium and N-methylglucamine salts dissolve in equal weights of water at 20C.

EXAMPLE l3 Suberic acid bis-( 3N-butyrolactamylmethyl-5-carboxy2 1,6- triiodoanilide) (Compound M) Calculated for C31H32[6NIOH' Found:

A thin layer chromatogram developed with isopropanol/isobutanol/ammonium hydroxide 2:5:3 had a spot at R; 0.45. The free acid was insoluble in water and chloroform. somewhat soluble in cold ethanol. very readily soluble in cold methanol and boiling ethanol. The sodium and N-methylglucamate salts dissolved in equal weights of water at 20C.

EXAMPLE 14 Other dicarboxylic acid bis-( 3-N-butyrolactamylmethyl-5-carboxy-2,4,6- triiodoanilides) (Compounds N to S) The acyl dichlorides of other dicarboxylic acids were converted by the method of Example 13 to corresponding anilidcs with 3-N-butyrolactamylmethyl-S-amino- 2,4.6-triiodobenzoic acid in an approximate mole ratio of l 2. The resulting compounds N to S were each identified by equivalent weight and elementary analysis and differed from Compound M only in the dicarboxylic acid radical. All were insoluble in water and chloroform and soluble in hot methanol and ethanol. Their sodium and N-methylglucamine salts dissolved in equal weights of water at 20C. Other properties are listed below.

TABLE IV Com- Dicarboxylic acid M.P.C. R; Note pound N Azelaic 220,sint.200 0.50 Sebacic 220225,sint.l95 0.59 (1) P Pimelic 240(decornp.) 0.40 (2) Q Z-Methyladipic 2l0,decomp.226 0.44 (1) R 4,7-Dioxadecanc- -l,l()-dioic 2l5220.sint.200 0.39 (2) S 4,8-Dioxaundecane- -l,ll-dioic 195.sint.l70 0.46 (l) Notes (l I Butanoh'giacial acetic acid/water 3:2:l (2| l-Butanol/ipropanol/ummonium hydroxide 5:2:3.

The acyl dichlorides required for preparing Corn pounds R and S were prepared from the corresponding dicarboxylic acids by gentle heating with thionyl chloride in a manner conventional in itself and described in more detail in our simultaneously filed application claiming the priority of Swiss application No.6626/68, reference also being had to J.A.C.S.70 (1948) 1333.

EXAMPLE l5 4,7-Dioxadecane-l ,10-dioic acid bis(3-N-5valerolactamylmethyl-S-carboxy-2,4,6- triiodoanilide) (Compound T) Homologs and analogs of the compounds described in Example 14 are prepared in substantially the same manner as exemplified by the following procedure.

18.35 g (0.03 Mole) 3-N-8-valerolactamylmethyl-S- amino 2,4,6-triiodobenzoic acid were prepared as described in Example 12 and dissolved in 30 ml dimethylacetamide. The solution was mixed with 4 g (0.016 mole) 4,7dioxadecane-1,-10-dioyl dichloride, prepared as described in Example 14, and the mixture was stirred at 95C. for three hours.

The solvent was evaporated at 2 mm Hg, and the resi due was washed with water and dissolved in dilute sodium hydroxide solution. Crude Compound T was precipitated with hydrochloric acid from the solution of its sodium salt. When recrystallized from approximately 100 ml isopopanol, the pure compound weighed 10.4 g. sintered at 200C. and melted at 225 230C. Its thin layer chromatogram developed with butanol/acetic acid/water 3:2:1 gave an R; value of 0.41.

Found:

The free acid is insoluble in water and chloroform and very readily soluble in cold methanol and ehtanol. The sodium and N-methylglucamine salts dissolve in equal weights of water at 20C.

EXAMPLE l6 Adipic acid bis(3-N-butyrolactamyl-5-carboxy-2.4,6 triiodoanilide) (Compound U) Calculated: Found:

12.37% Cl; 9.77% N 3.93 8

l 12 g B-y-Chlorobutyrylamino-S-nitrobenzoic acid (0.375 mole) were dissolved in 550 ml water containing 74 g KOH (1.35 mole), and the solution was left to stand a few hours to cause practically complete ring closure as evidenced by the presence of an equivalent concentration of chlorine ions. It was then diluted with 500 ml water and mixed with 150 ml 18% hydrochloric acid to precipitate crude S-N-butyrolactamyl-S nitrobenzoic acid. It was purified by dissolution in sodium hydroxide solution and reprecipitation with hydrochloric acid, a second conversion to the sodium salt with an equivalent amount of sodium hydroxide solution, salting out of the sodium salt with sodium chloride, and decomposition of the sodium salt. The pure 3-N-butyrolactamyl-5-nitrobenzoic acid weighed 63.5 g (67.5% yield) and melted at 245C. It was identified by elementary analysis:

A chromatogram on silica gel developed with hutyl acetate/glacial acetic acid/water 5: l :1 gave an R, value of 0.55.

25 g 3-N-Butyrolactamyl-S-nitrobenzoic acid (0.1 mole) were dissolved in 400 ml water and ml N sodium hydroxide and hydrogenated at room temperature in the presence of 2.5 g 10% palladium-carbon catalyst. After an amount of hydrogen sufficient for hydro genation of the nitro group had been consumed, the catalyst was removed by filtration, and the filtrate containing sodium 3-Nbutyrolactamy1-5-aminobenzoic acid was poured into 8 liters water containing 50 ml 36% hydrochloric acid. 350 ml N KlCl solution were added to the acidic mixture in a thin stream with agitation over a period of 20 minutes, and the iodation reaction was permitted to go to completion in 15 hours at ambient temperature with continuing agitation.

The crude 3Nbutyrolactamyl-5-amino-2,4,6- triiodobenzoic acid so obtained was dissolved in sodium hydroxide solution. precipitated with hydrochlo ric acid, and again dissolved in an equivalent amount of sodium hydroxide solution. The sodium salt was salted out with sodium chloride. and the latter was dis solved in water and decomposed with hydrochloric.

Calculated: Found.

An aliquot of the above hydrogenation mixture was adjusted to pH 4. to precipitate a sample of the 3-N butyrolactamyl-S-aminobenzoic acid. it melted at 220C. and was identified by elementary analysis:

Calculated. 49% H; 12. Found. .69 12.62

59 99% C; sum

crystallization of the salt which was recovered from the mother liquor and dissolved in water. The solution was poured into 3% aqueous hydrochloric acid at 70C. to precipitate the pure Compound U which was recovered in an amount of 12.8 g (49% yield), melted at 270C. and had an R, value of 0.35 (butanol/glacial acetic acid/water 3:211). It is practically insoluble in water and only sparingly soluble in methanol. ethanol, and chloroform. it was identified by its equivalent weight and elementary analysis:

Calculated for C H LJQ CL Eq.wt. 653. 25.75% C; 58.31% I Found: 652.5 25.50 57.90

The sodium and N-methylglucamine salts of Compound U dissolve in equal weights of water at C.

EXAMPLE 17 Other dicarboxylic acid bis( BN-butyrolactamyl-5-carboxy-2,4.6- triiodoanilides) (Compound V W) Anilides homologous to Compound U were prepared from 3-N-butyrolactamyl-5-amino-2,4.6- triiodobenzoic acid and the acyl dichlorides of pimelic and sebacic acid in the same manner as described in Example lo. Their melting points and R, values (butanoli'acetic acid/water 3:2: I are listed in Table V. Like Compound U. Compounds 'v' and W inso'uble in water, whereas their sodium and N-methylglucamine salts dissolve very readily in water at room temperaturc. Both free acids were identified by their equivalent weights and elementary analysis.

TABLE V Con1- Dicur'ooxylic acid M PFC R, pound V Pimclic 353 0.39 W Schucic 153 0.52

EXAMPLE l8 3-N-Butyrolactamyl-Smcetylamino-methylQAbtriiodohenzoic acid (Compound X) 8.4 g {0.06 Mole) fi-cblorobutyryl chloride were added dropwise with agitation to a solution o 29.3 g (0.05 mole) 3-amino-5acetylaminomethyl-2,4.6 triiodobenzoic acid in ml dimethylacetamide over a period of 10 minutes. and the mixture so obtained was stirred three hours at C., cooled. and stirred into 600 g ice water, whereby 27 g 3-8-chlorobutyrylamino- 5-acetylarninomethyl 2.4 o-triiodobenzoic acid were precipitated. M.P.l45 147C. (dccomp) 20.7 g Thereof were dissolved in 60 ml 2-N aqueous potassium hydroxide. and the solution was stored at room temperature for about 20 hours, whereupon it was diluted with 250 ml water. and strongly acidified with hydrochloric acid. The crude Compound X precipitated thereby was recovered by filtration and dissolved in dilute aqueous ammonium hydroxide. The solution was adjusted to pH 541. decolorized with active carbon, heated to 50C.. and added dropwise to 200 ml dilute hydrochloric acid having the same temperature to precipitate pure Compound X in an amount of 16.5 g (84% yield).

Compound X has a melting point of 250C. and an R, value of 0.59 with butanol/glacial acetic acid/water 3:211. it is insoluble in water. whereas the sodium and N-methylglucamine salts dissolve at a rate of more that. g per dl in water at 20C.

Compound X was identified by its equivalent weight and elementary analysis:

Calculated for C H L Ni Oc Eqwt. (154; 25.719? 58.22%

C; Found: 646 25.59 53.1 l

EXAMPLE 19 3-(Morpholinon-3'-yl-4')-5acetylaminomethylifi,6- triiodobenzoic acid (Compound Z) in the manner described in Example l8, 29.3 g 3- amino-5-acetylaminomethyl-2,4.b-triiodobenzoic acid in 60 ml dimethylacetarnide were reacted with 9.6 g B-chloroethoxyacetyl chloride. There were obtained 24 g 3-B-chloroethoxyacetylamino5-acetylaminomethyl- 2.4,6-triiodobenzoic acid melting at 233 235C. (decomp.) of which 23.5 g were dissolved in 60 ml 2N potassium hydroxide solution. The solution was stored for about 20 hours at room temperature. and Compound Z was thereafter precipitated and purified as described above.

The amount of pure Compound Z recovered was 19.3 g (879? yield). M.P.230C. (decompj R,= 0 61. The compound was identified by its equivalent weight and elementary analysis:

Calculated for C H l N O Eq.wt. 670; 25.10% 56.03%l

weights of water at 20C.

EXAMPLE 20 5-N-alkyl-derivatives of Compounds G and .l (Compounds GA, GB, JA, and 18) A solution of 5.35 g methyl iodide (0.0375 mole) in 3 ml acetone was added dropwise with agitation to a solution of 16.35 g Compound .I (0.025 mole; see Example in 25 ml N potassium hydroxide at room temperature. After three hours, the mixture was heated to 40 45C. It was held at this temperature for a few hours, cooled, diluted with 60 ml water, and extracted twice with 25 ml diethyl ether. The aqueous phase was purged of ether in a vacuum and thereafter poured into l ml 3% hydrochloric acid to precipitate crude 3-N- Butyrolactamylmethyh5-N-methylacetylamino-2,4,6- triiodobenzoic acid (Compound JA).

The crude material was dissolved in 40 ml boiling methanol, and the solution was mixed with an equivalent amount of morpholine and left to stand for a few hours. A tacky, amorphous precipitate was formed and removed by filtration. The filtrate was decolorized with active carbon, and 60 ml diethyl ether was added to precipitate the morpholine salt of Compound JA. It was dissolved in 50 ml water, and the solution was poured into 100 ml 3% hydrochloric acid. The precipitated pure Compound JA was recovered in an amount of 8.6 g (52% yield). M.P.280C. R,=0.40 (ethyl acetate/isopropanol/ammonium hydroxide ll:7:4).

Calculated for c,,u,,|,1v,o,= Eq.wt. 668; 26.96% 57.00% I Found: 676 26.93 56.94

The free acid is practically insoluble in water, the sodium and N-methylglucamine salts readily dissolve in water at room temperature.

3-N Butyrolactamylmethyl-S-N-ethylacetylamino- 2,4,6-triiodobenzoic acid (Compound 13) was obtained in a similar yield when ethyl iodide in the preceding procedure was substituted for methyl iodide,

and the alkylation temperature was raised to 55 255C, and having an R, value of 0.68 with the lastmentioned solvent system.

For each of Compounds 18, GA, and GB, the equivalent weightwas determined and an elementary analysis was made. The values obtained closely agreed with those calculated from the assumed formulas.

EXAMPLE 2] An intravenously injectable solution was prepared according to the following prescription:

Compound J (Example l0) 5L6 g N-Methylglucamine 13.89 g Sodium hydroxide 0.316 g Disodium edetate 0.004 g Bi-distilled water to make l00 ml The chelating agent was first dissolved in a small portion of the water, the other solutes were added in the listed sequence with stirring and dissolved, and the con centrate so obtained was adjusted to pH 7.1 i 0.2. The remainder of the water was then added, and the solution was subjected to ultrafiltration, transferred to 20 ml vials, and sterilized.

It contained 300 mg iodine per ml, and was successfully used for visualizing the urinary tract after intravenous injection in an amount corresponding to approximately 200 mg of the radiopaque compound per kg body weight. Similar success was had with other radiopaque compounds of the invention containing one trioodobenzoic acid moiety in solutions containing 30% to 60% of the active agents and 150 to 350 mg iodine per ml.

R in these compounds was hydrogen, acylamino, N- alkylacylamino, acrylaminomethyl, N-alkylcarbamyl, or the radical of a lactam or of morpholinone.

The same compounds, when employed in solutions containing 300 to 450 mg iodine per milliliter (500 to 900 mg/ml active agent) have been used for angiogra phy and angiocardiography by intraarterial injection, the prescription of Example 22 being representative of such solutions.

EXAMPLE 22 Compound N (Example 14) 721 N-Methylglucamine [76 Sodium hydroxide 8 Disodium edetate 0.04 Bi-distilled water 1,000

EODODMUH to make The solution was prepared as described in Example 21, adjusted to pH 7.] t 0.2, ultrafiltered, transferred to l0 ml and 20 ml vials and to rubber capped bottles of EXAMPLE 23 An intravenously injectable solution was prepared according to the following prescription:

Compound R (Example 14) 550 g N-Methylglucamine l03 g Sodium hydroxide 12 g Disodium edetate 0.04 g Bidistillcd water to make 1.000 ml he ingredients were combined as described in Examile 21, the solution was adjusted to pH 7.0 i (ll, ulrafiltered. and sterilized in 20 ml vials for intravenous njection preceding cholecystography. It contained 300 ng iodine per milliliterv The amount required for visuilizing a human gall bladder corresponded to about 4 o 12 g of the active agent, a dosage of 8 g giving satisactory contrast in most adult patients.

Equally satisfactory results were achieved by pareneral application of the other compounds of the invenion having two triiodobenzoic acid moieties in each nolecule, the iodine content of the solutions being beween 150 and 350 mg per milliliter.

What is claimed is:

l. A compound of the formula R R' wherein R is CO 1 N or R is hydrogen, R

R, is alkylene having 2 or 3 carbon atoms;

R2 is 2)n;

R is hydrogen or acetyl;

R, is hydrogen, methyl, or RNH- COR CO,

R being hydrogen when R is RNHCOR- 5"C0 R is alkylene or polyoxaalkylene having 4 to 8 car bon atoms;

a is either zero or one; and

A is hydrogen or a non-toxic metal or amine, the compound being water-soluble when A is said metal or amine.

2. A compound as set forth in claim I, wherein A is iydrogen, sodium, lithium, or alkanolamine.

3. A compound as set forth in claim 1, wherein R is -C H,, a is zero, and R is acetylamino.

4. A compound as set forth in claim 1, wherein R, is C,H,, a is zero, R is acetylaminomethyl.

5. A compound as set forth in claim I, wherein R is C H,, a is one, and R is N-methyl-N-acetylamino.

6. A compound as set forth in claim 1, wherein R, is -C H,, a is one, and R is RNHC0R -CO.

7. A compound as set forth in claim 6, wherein R is z)1-- 8. A compound as set forth in claim 6, wherein R is (CH2)B""- 9. A compound as set forth in claim 6, wherein R, is (CH2)G- 10. A compound as set forth in claim 6, wherein R, is (CH2)5.

11. A compound as set forth in claim 6, wherein R is z)z-- 2)2 z)z- 12. A compound as set forth in claim 6, wherein R is 2)2 2)a 2)2- 13. A compound as set forth in claim 2, wherein R, is (CH;);,, a is one, and R, is R-NH-CO-R- =,-CO.

14. A compound as set forth in claim 13, wherein R is 15. A compound as set forth in claim 2, wherein R, is -(CH a is zero, and R, is R-NH-COR- COv 16. A compound as set forth in claim 15, wherein R is (CH 17. A compound as set forth in claim 15, wherein R is (CH 18. A compound as set forth in claim 15, wherein R is (CH2)3.

19. The compound of the formula COOH 

1. A COMPOUND OF THE FORMULA R - R'' WHEREIN R IS
 2. A compound as set forth in claim 1, wherein A is hydrogen, sodium, lithium, or alkanolamine.
 3. A compound as set forth in claim 1, wherein R1 is -C2H4-, a is zero, and R'' is acetylamino.
 4. A compound as set forth in claim 1, wherein R1 is -C2H4-, a is zero, R'' is acetylaminomethyl.
 5. A compound as set forth in claim 1, wherein R1 is -C2H4-, a is one, and R'' is N-mEthyl-N-acetylamino.
 6. A compound as set forth in claim 1, wherein R1 is -C2H4-, a is one, and R4 is R-NH-CO-R5-CO-.
 7. A compound as set forth in claim 6, wherein R5 is -(CH2)7-.
 8. A compound as set forth in claim 6, wherein R5 is -(CH2)8-.
 9. A compound as set forth in claim 6, wherein R5 is -(CH2)6-.
 10. A compound as set forth in claim 6, wherein R5 is -(CH2)5-.
 11. A compound as set forth in claim 6, wherein R5 is -(CH2)2-O-(CH2)2-O-(CH2)2-.
 12. A compound as set forth in claim 6, wherein R5 is -(CH2)2-O-(CH2)3-O-(CH2)2-.
 13. A compound as set forth in claim 2, wherein R1 is -(CH2)3-, a is one, and R4 is R-NH-CO-R5-CO-.
 14. A compound as set forth in claim 13, wherein R5 is -(CH2)2-O-(CH2)-O-(CH2)2-.
 15. A compound as set forth in claim 2, wherein R1 is -(CH2)2-, a is zero, and R4 is R-NH-CO-R5-CO-.
 16. A compound as set forth in claim 15, wherein R5 is -(CH2)4.
 17. A compound as set forth in claim 15, wherein R5 is -(CH2)5.
 18. A compound as set forth in claim 15, wherein R5 is -(CH2)8.
 19. The compound of the formula 